MLL was first identified because it is involved in chromosomal translocations that result in leukemia. MLL is required for maintaining the proper expression of target genes, including some of the clustered HOX genes. There is growing evidence that MLL regulates gene expression by modulating chromatin structure via activity of some of its protein domains as well as through additional proteins that it recruits. Our data demonstrate that MLL protects specific CpG DNA sequences in the Hoxa9 target gene locus from methylation, thereby allowing gene expression, both of canonical Hoxa9 and of a microRNA precursor. We therefore propose a novel model of MLL function. We propose that MLL maintains the potential to express its target genes by preventing CpG island methylation during development. MLL protection from CpG methylation keeps the locus "open" and permissive for gene expression through subsequent cell divisions. This mark is not easily changed and, therefore, can function to maintain memory of previous gene expression. We will determine the role of MLL in protection from DNA methylation, the specific role of the MLL CpG DNA binding CXXC domain to MLL fusion function, and of a specific microRNA to MLL leukemogenesis. PUBLIC HEALTH RELEVANCE: MLL is a gene that, when involved in chromosome rearrangements, causes leukemia with a very poor prognosis. We have determined a new function of MLL with regard to how it regulates expression of other genes. We wish to further study the details of this new mechanism to advance our understanding of how MLL normally functions and how this is changed in MLL leukemia.